Sitagliptin is a potent, orally active dipeptidyl peptidase IV (DPP-IV) inhibitor used for the treatment of type II diabetes (Drugs of Today 2007; 43:801-814). There is a number of substrates beyond metabolic control that DPP-IV cleaves, and therefore inhibit their action, including hormones, neuropeptides, and chemokines. DPP-IV inhibitors prolong the action of hormone YY, neuropeptides such as substance P, and macrophage-derived chemokines. Potential adverse effects resulting from the prolongation of these messengers include inflammation (effect on substance P), increased blood pressure (effect on neuropeptide Y), and allergic reactions (effect on chemokines). Particularly, lower serum DPP-IV activity is related to depressive and anxiety symptoms and immune activation in patients with hepatitis C (Molecular Psychiatry 2001; 6:475-480) and to the neurogenic inflammation induced by substance P in chronic rhinosinusitis (The FASEB Journal 2002; 16:1132-1134). Furthermore, inhibition of DPP-IV may be a trigger of prostate cancer metastasis (Clin Exp Metastasis 2008; 25:765-776 and Int J Cancer 2004; 109:855-866) and inhibitors of DPP-IV have the potential to interfere with chemokine-mediated effects including but not limited to allergy (J Immunol 2008; 181:1120-1127).
A combination therapy of sitagliptin with the well established active ingredient of diabetes management metformin HCl provides even more effective treatment of type II diabetes (Drugs Today 2008; 44:303-314). Although metformin is effective at lowering blood glucose levels, its use is associated with gastrointestinal (GI) adverse effects, particularly diarrhea and nausea (Expert Opin Pharmacother 2006; 7:803-809). These adverse effects may limit the tolerated dose of metformin and cause patients to discontinue therapy.
Most currently available metformin formulations are immediate-release (IR) products, which release the entire drug within 1-2 h after dosing, resulting in high drug concentrations in the GI tract and consequently in undesired adverse effects.
WO 2009/111200 discloses pharmaceutical formulations comprising an inner core tablet composition comprising metformin hydrochloride. The inner core is coated with a sustained-release polymer and further comprises a coating comprising an immediate release composition of sitagliptin. When dissolving such tablets, firstly the sitagliptin from the immediate release coating is released. After dissolution of the immediate release coating, the sustained-release of the metformin hydrochloride starts.
EP 1 537 880 A1 discloses sustained release formulations of DPP-IV inhibitors in general, including sitagliptin. Such sustained release formulations comprise DPP-IV inhibitor and hydrophilic polymer.
WO 2009/099734 discloses pharmaceutical compositions providing an extended release of metformin and an immediate release of sitagliptin. The tablet core is comprised of metformin and an extended release excipient (HPMC). The tablet core is then coated with immediate release polymer comprising sitagliptin.
Although pharmaceutical compositions comprising metformin and sitagliptin exist, there is still a need for improved pharmaceutical compositions comprising metformin and sitagliptin as well as an improved process for preparing such preparations.